title: Role of SIRT3 in the regulation of redox balance during oral carcinogenesis.
abstract: BACKGROUND
  Sirtuins (SIRT1-7) are a family of NAD-dependent deacetylases, which play an important role in regulating cancer tumorigenesis; however, their role in oral cancer has been controversial. SIRT3 is localized in the mitochondria, where it deacetylates and activates several enzymes involved in cellular redox balance and defense against oxidative damage.
  
  
  RESULTS
  We found that compared with normal human oral keratinocytes (HOK), SIRT3 is highly expressed in oral squamous cell carcinoma (OSCC) cell lines, but the enzymatic deacetylation is significantly reduced. We also sequenced the entire coding region of SIRT3 and found the same mutation in 2 different OSCC cell lines. This point mutation is located in close proximity to the active site of deacetylase in the SIRT3 protein, and reduces the overall enzymatic efficiency of deacetylation. Furthermore, up-regulation of SIRT3 inhibited the cell growth of OSCCs and decreased the levels of basal reactive oxygen species (ROS) in both OSCC lines. To verify that the SIRT3 sequence variation was associated with oral carcinogenesis, we sequenced the SIRT3 gene from 21 OSCC patients, and 5 of the 21 patients (23.8%) carried the heterozygous missense mutation, p.Val208Ile. The heterozygous missense mutation in these patients was present in gremlin DNA isolated from both normal and tumor tissues.
  
  
  CONCLUSIONS
  Our findings provide a valuable insight into the potential role of SIRT3 in the development of oral squamous cell carcinoma, by showing that a non-synonymous point mutation in SIRT3 contributes to reduced catalytic activity of the protein and affects redox balance in OSCCs.
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health, Research Institutes, No, 35, Keyan Road, Zhunan, Miaoli 35053, Taiwan.
authors.forename: I-Chieh
authors.initials: IC
authors.lastname: Chen
authors.forename: Wei-Fan
authors.initials: WF
authors.lastname: Chiang
authors.forename: Shyun-Yeu
authors.initials: SY
authors.lastname: Liu
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Chen
authors.forename: Hung-Che
authors.initials: HC
authors.lastname: Chiang
mesh_terms: D001483:Base Sequence; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression; D014644:Genetic Variation; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D056566:Sirtuin 3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D056566:Sirtuin 3